Exelixis, Inc. Message Board

  • hbomb57108 hbomb57108 May 16, 2013 11:10 PM Flag

    Goldman Sachs transcript relevant to comet placebo estimation

    So the key metrics for the drug arm of Cougar 301 is the median time for drug treatment, which was eight months and the median time for overall survival, which was 15 months. And the way to look at it and the impact and how it impacts cabos, the COMET trial is that the drug treated from Cougar 301 corresponds to the placebo arm for COMET-1. In that patients would come on post-tax, post-abi. So as they had progressed on abi, the clock starts in terms of the survival post abi in the placebo arm.

    So it’s a conservative estimate of seven months. Obviously there will be time for COMET-1 to wash out onto site, go through screening and those kinds of things. So we think it’s a very conservative way to view the arm around the placebo group and have certainly gotten a lot of feedback from our key KOLs, Dr. Smith, Dr. de Bono, Kareem Fizazi and others to be able to kind of make sure that makes sense for us in terms of that.

    On the cabo arm, we had from the NRE, we had several metrics of durability of response. The bone scan response had about a 5.5-month duration of response, which I think we are very pleased to see. Again, what would be the argument, it could be seen at the sub-optimal dose in terms of the 100 mg does. So we see that being longer with the lower more stable dose, number one.

    The PFS for this late population, for both the overall group, as well as the abi preceded group was about 4.4, 4.5 months. So very good overall durability of progression free survival as measured by recess, which looks at all types of metastases, soft tissue restoral, as well as bone disease.

    The one point I would make there is that we were enrolling patients with ligaments in the NRE and those patients will not be allowed to enroll in the COMET trail. So we will focus on patients with bone disease, predominate bone disease or bone disease and with no disease as well.

    Terence Flynn - Goldman Sachs
    Okay. So net-net comparing the I guess the 4.4 months from the NRE to the, I guess eight months treatment duration in your COMET study, you are saying essentially if we have a lower dose of cabo, your treatment duration might be longer to the target. Is there a patient been on drug longer...

    Mike Morrissey - Chief Executive Officer
    Yes exactly.

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    • And the way to look at it and the impact and how it impacts cabos, the COMET trial is that the drug treated from Cougar 301 corresponds to the placebo arm for COMET-1. In that patients would come on post-tax, post-abi. So as they had progressed on abi, the clock starts in terms of the survival post abi in the placebo arm.

      Yes, this is where the 7 month assumption for the Comet arms comes from. It isn't perfect though. First, it needs to be pointed out that with Abi moving pre-chemo, a growing percentage of the patients will be treated Abi first and then Taxotere. How that will affect their outcome is unknown.

      None of the NRE patients initially received an initial optimum Cabo dose. 93 were dosed high at 100mg and 51 dosed low at 40mg. 24% of the 100mg dose patients were actually double chemo refractory, having also received Cabazitaxel.

      Based on duration of bone scan response (5.5 months) and PFS (4.2 months) I am guessing that the median time on treatment is about 5 months. The Comet's, especially Comet 2, are recruiting the most refractory population ever evaluated in PC. For comparison, Taxotere extended survival 2.4 months (18.9 vs 16.4). Post chemo Abi 3.9 months (14.8 vs 10.9), Cabzitaxel by 2.4 months (15.1 vs 12.7), Provenge 4.1 months (25.8 vs 21.7) and Alpharadin 2.8 months (14.0 vs 11.2).

      Interestingly, the Alpharadin population was symptomatic bone mets, no visceral mets and only 58% chemo refractory. No mention of prior Abi.

      When the actual presentation of the Scher abstract is made and also at the June investor briefing, we will get more detail on subgroup analysis. Of interest will be 100mg vs 40mg data; double Abi/Tax refractory data; Bone/visceral vs bone only; etc...

      • 2 Replies to erniewerner
      • Thanks for the summary Ernie.

        I really hope EXEL has an ace up their sleeve for the Sher presentation but I am not sure where it would come from. The subgroup data will be interesting but sample size will be even smaller than the RDT. I sure hope time on treatment is longer in the 40 mg group than 100 mg. I am not expecting a big difference though. The OS of 10.8 months for Cabo is a small number in my mind. It's the smallest number of any in the comparison you noted. It doesn't justify the confidence they are selling. It will be interesting hear Sher's talk and how it is spun at the ASCO investor briefing. In my mind the OS data certainly adds a lot of uncertainty to the COMETs picture.

        I am curious to know how the 10.8 median OS data has changed your thinking about EXEL and Cabo in mCRPC? Is there anything specific that you are looking to see at ASCO?

      • thanks for the summary Ernie. nice thing about your compilation is that none of the approved therapeutics is a kinase inhibitor. with a completely different MOA it's easy to see how cabo could be combined with Xtandi as is being done with Abi. hopefully there will be significant synergies with the cabo-abi combo. it should even be possible (eventually) to add one of the cytoxics for some of these really late stage patients.

    • This is the CEO talking so I'll take it w/ a grain of salt, but what he says about a shorter period of Cabo exposure is interesting. In theory, AR deprivation will cause tumors to adapt with c-Met over-expression, and presented with Cabo, cancer cells will need time to readjust, maybe back to AR expression as evidenced by the cross talk?! So the lower dosing and the post androgen deprivation may help Cabo in COMET-1. In the end, I suspect that the ideal course of treatment will be style of dosing present in the combo trials with one of the anti-androgens.

      • 1 Reply to wildbiftek
      • "Interestingly, the Alpharadin population was symptomatic bone mets, no visceral mets and only 58% chemo refractory. No mention of prior Abi. "

        Aha, that symptomatic population explains why the comparator arm OS was so short in Alpharadin trial.

        The abi trial had a fair amount of symptomatic with approx 45% with 4 BPI.(89% bone metastasis)

        Enzalutamide on the other hand, had approx 25% with 4 BPI.(90% bone metastasis)

        Here is an interesting take on those sympomatic patients on Enzalutamide

        Pain was assessed by three methods: Brief Pain Inventory Short Form (BPI-SF, baseline and week 13); self-reported pain diaries at baseline and weekly, including analgesic use and worst pain for 7-day period; and Functional Assessment of Cancer Therapy–Prostate (FACT-P) questionnaire at baseline and week 13.

        On the BPI-SF, enzalutamide reduced pain severity; patients taking enzalutamide improved pain scores by 7.5%, while those on placebo had worsening pain by 23% (P 30% reduction in mean pain score at week 13 vs baseline without a 30% increase in analgesic use) was achieved in 45% of the enzalutamide arm versus 7% of the placebo arm (P = .0079).

        On the FACT-P, the median for time to pain progression had not yet been reached in the enzalutamide arm versus 13.8 months in the placebo arm, representing a risk reduction of 44% (P = .0004). The total QoL score on the FACT-P showed that QoL was dramatically improved in patients taking enzalutamide: 43% had improvement in QoL versus 18% in the placebo arm. Significant improvements were seen in all QoL domains for enzalutamide compared with placebo (P

    • $$$$
      Hbomb,
      If I read you correctly, aren't we further confounding our OS data by continued dose finding, dose reduction, and soft tissue considerations. IOW - stay with a bony mets pop, acknowledge & maintain an aptly efficacious dosage, keep the focus on the biomarker work-ups...perhaps even let them be your guide.
      Isn't Mr Market being a bit unreceptive of this heavily pretreated, very sick patient group that actually did pretty derned good - extent of advanced disease taken into consideration?

      • 1 Reply to wilderguide
      • "If I read you correctly, aren't we further confounding our OS data by continued dose finding, dose reduction, and soft tissue considerations. IOW - stay with a bony mets pop, acknowledge & maintain an aptly efficacious dosage, keep the focus on the biomarker work-ups...perhaps even let them be your guide.
        Isn't Mr Market being a bit unreceptive of this heavily pretreated, very sick patient group that actually did pretty derned good - extent of advanced disease taken into consideration?"

        I really don't have anything more to add than what Ernie has already stated. I was hoping for a bit better OS. That said, I still think odds are COMET 1 will demonstrate statsig OS benefit. I am cautiously optimistic. I am reserve most of my comments until I see subgroup analysis June 2.

 
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